Diabetes mellitus (non-insulin-dependent, or Type II, diabetes) is a group of disorders characterized by high blood glucose levels (hyperglycemia) that generally involves an impaired insulin secretory response to glucose as well as insulin resistance. The mechanism of insulin action is impaired in diabetes, leading to less glucose transport into muscle and fat. The elevated blood glucose levels that result can lead to a variety of serious health problems.
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic amine that functions both as a neurotransmitter in the mammalian central nervous system and as a hormone in the periphery, where most of it is produced (Gershon et al., 1990, Neuropsychopharmacology, 3:385-395). Serotonin is generated through an enzymatic cascade in which L-tryptophan is converted into L-5-hydroxytryptophan by an enzyme called tryptophan hydroxylase (TPH). This intermediate product is then converted to serotonin by an aromatic L-amino acid decarboxylase. There are two TPH encoding genes, TPH1 and TPH2, which are 71% identical in amino acid sequence and about 90% similar in their catalytic domains. While TPH1 controls serotonin synthesis in the periphery, TPH2 is responsible for serotonin synthesis in the brain (Walther et al., 2003, Science 299:76). Given that serotonin cannot cross the blood-brain barrier, these two genes are therefore solely responsible for regulating the level of this molecule in the periphery and in the brain, respectively.
TPH1 is expressed almost exclusively in cells of the duodenum, and it is responsible for the synthesis of peripheral serotonin, which represents 95% of total serotonin (Gershon & Tack, 2007, Gastroenterology 132:397-414). TPH1 expression in any tissues other than duodenum is at least 100-1000 fold lower. Thus, TPH1 can be viewed as a duodenum-specific gene and peripheral serotonin production as a duodenum-specific process.
Besides its role as a neuromediator, and because of its abundance in the general circulation, serotonin has been implicated in a variety of developmental and physiological processes in peripheral tissues, including heart development, gastrointestinal movement, liver regeneration and mammary gland development (Lesurtel et al., 2006, Science, 312:104-107; Matsuda et al., 2004, Dev. Cell, 6:193-203; Nebigil et al., 2000, Proc. Natl. Acad. Sci. USA 97:9508-9513). To carry out its functions, serotonin can bind to at least 14 receptors, most of them being G-protein coupled receptors (GPCRs). One or several serotonin receptors are present in most cell types.
Mice genetically deficient for the TPH1 gene (“knockout mice”) have been reported. In one case, the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. In another, the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin (Côté et al., 2003, Proc. Natl. Acad. Sci. USA 100:13525-13530).
International Patent Application No. PCT/US2009/038817, published as WO 2009/123978, the disclosure of which is incorporated herein in its entirety, is directed to methods of diagnosing, preventing, and treating bone mass diseases using therapeutic agents for lowering or increasing serum serotonin levels. International Patent Application No. PCT/US2009/064383, published as WO 2010/056992, the disclosure of which is incorporated herein in its entirety, is also directed to methods of diagnosing, preventing, and treating bone mass diseases using therapeutic agents for lowering or increasing serum serotonin levels.
LP-533401 is an inhibitor of TPH1 having the following structure:

See, e.g., Liu et al., 2008, J. Pharmacol. Exp. Ther. 325:47-55.
Other inhibitors of TPH1 are disclosed in International Patent Publications WO 09/123978; WO 10/056992; WO 08/073933; WO 09/002964; WO 09/002970; WO 09/009561; WO 09/014972; WO 09/029499; WO 09/042733; WO 09/048864; WO 10/065333; and WO 07/089335. Other disclosures of TPH1 inhibitors appear in U.S. Pat. No. 7,553,840 and U.S. Patent Application Publications Nos. US 2007/0191370; US 2008/0153852; US 2009/0005381; US 2009/0005382; US 2009/0029993; US 2009/0054308; US 2009/0062540; US 2009/0088447; and US 2009/0099206.